The proposed research will use the thymidine analog 5-bromodeoxyuridine (BUDR) as a probe to study genetic activities and malignant transformation in mammalian cells. The molecular mechanisms by which BUDR suppresses the differentiation of Syrian hamster melanoma cells will be studied. Similar studies also will be carried out with mouse erythroleukemia cells. In addition, the mechanism by which deoxycytidine reverses the effects of BUDR will be studied. The experiments on malignant transformation will be based on the unique properties of a variant line of Syrian hamster melanoma cells that we have isolated and which expresses the transformed phenotype only in the presence of BUDR. Attempts will be made to develop this line as a system of conditional malignancy. Other studies will focus on the mechanisms of mutagenesis by halogenated thymidine analogs and the mechanisms of cellular resistance to the analogs. In addition to BUDR, 5-iododeoxyuridine and 5-chlorodeoxyuridine will be used.